Transdermal treatment with 5-alpha reductase inhibitors

ABSTRACT

The instant invention involves a method of treating and/or reversing androgenic alopecia and promoting hair growth, and methods of treating acne vulgaris, seborrhea, and female hirsutism, by administering to a patient in need of such treatment a 5α-reductase 2 inhibitor, such as finasteride, in a dosage amount under 5 mgs/day.

[0001] This application is a continuation-in-part of Ser. No. 08/138,520filed Oct. 15, 1993.

[0002] The present invention is concerned with the treatment ofandrogenic alopecia, including male pattern baldness, with compoundsthat are 5-alpha reductase isozyme 2 inhibitors.

BACKGROUND OF THE INVENTION

[0003] Certain undesirable physiological manifestations, such as acnevulgaris, seborrhea, female hirsutism, androgenic alopecia whichincludes female and male pattern bkdness, and benign prostatichyperplasia, are the result of hyperandrogenic stimulation caused by anexcessive accumulation of testosterone (“T”) or similar androgenichormones in the metabolic system. Early attempts to provide achemotherapeutic agent to counter the undesirable results ofhyperandrogenicity resulted in the discovery of several steroidalantiandrogens having undesirable hormonal activities of their own. Theestrogens, for example, not only counteract the effect of the androgensbut have a feminizing effect as well. Non-steroidal antiandrogens havealso been developed, for example,4′-nitro-3′-trifluoromethyl-isobutyranilide. See Neri, et al.,Endocrinol. 1972, 91 (2). However, these products, though devoid ofhormonal effects, compete with all natural androgens for receptor sites,and hence have a tendency to feminize a male host or the male fetus of afemale host and/or initiate feed-back effects which would causehyperstimulation of the testes.

[0004] The principal mediator of androgenic activity in some targetorgans, e.g. the prostate, is 5α-dihydrotestosterone (“DHT”), formedlocally in the target organ by the action of testosterone-5α-reductase.Inhibitors of testosterone-5α-reductase will serve to prevent or lessensymptoms of hyperandrogenic stimulation in these organs. See especiallyU.S. Pat. No. 4,377,584 assigned to Merck & Co., Inc., issued Mar. 22,1983. It is now known that a second 5α-reductase isozyme exists, whichinteracts with skin tissues, especially in scalp tissues. See, e.g., G.Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791(November 1992). The isozyme that principally interacts in skin tissuesis conventionally designated as 5α-reductase 1 (or 5α-reductase type 1),while the isozyme that principally interacts within the prostatictissues is designated as 5α-reductase 2 (or 5α-reductase type 2).

[0005] Finasteride(17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-ene-3-one), which ismarketed by Merck & Co., Inc. under the tradename PROSCAR®, is aninhibitor of 5α-reductase 2 and is known to be useful for the treatmentof hyperandrogenic conditions. See e.g., U.S. Pat. No. 4,760,071.Finasteride is currently marketed in the United States and worldwide forthe treatment of benign prostatic hyperplasia. Finasteride's utility inthe treatment of androgenic alopecia and prostatic carcinoma is alsodisclosed in the following documents: EP 0 285,382, published 5 October1988; EP 0 285 383, published Oct 5, 1988; Canadian Patent no.1,302,277; and Canadian Patent no. 1,302,276. The specific dosagesexemplified in the above-noted disclosures varied from 5 to 2000 mg perpatient per day.

[0006] In the treatment of androgenic alopecia, which includes bothfemale and male pattern baldness, and other hyperandrogenic conditions,it would be desirable to administer the lowest dosage possible of apharmaceutical compound to a patient and still maintain therapeuticefficacy. Applicants have surprisingly and unexpectedly discovered thata low daily dosage of a 5α-reductase 2 inhibitor is particularly usefulin the treatment of androgenic alopecia. Furthermore, a low daily dosageof a 5α-reductase 2 inhibitor may also be particularly useful in thetreatment of the hyperandrogenic conditions of acne vulgaris, seborrhea,female hirsutism, and polycystic ovary syndrome.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The instant invention involves a method of treating and/orreversing androgenic alopecia and promoting hair growth, and methods oftreating acne vulgaris, seborrhea, and female hirsutism, which comprisesadministering to a patient in need of such treatment a 5α-reductase 2inhibitor in a dosage amount under 5 mgs/day. In one embodiment of thisinvention, the 5α-reductase 2 inhibitor is administered in a dosageamount of from 0.01 to 3.0 mgs/day. In one class of this embodiment, the5α-reductase 2 inhibitor is administered in a dosage amount of from 0.05to 1.0 mg/day, and in a sub-class of this embodiment, the 5α-reductase 2inhibitor is administered in dosage amounts of about 0.05 to 0.2 mg/day.Illustrating this subclass are dosage amounts of about 0.05, 0.1, 0.15and 0.2 mg/day. Exemplifying the sub-class are dosages of 0.05 and 0.2mg/day. Compounds which are inhibitors of 5α-reductase 2 can bedetermined by employing the assay described below in Example 3.

[0008] In a second embodiment of this invention, the method of treatingandrogenic alopecia comprises administration of 5α-reductase 2 inhibitorcompounds which have the structural formula I

[0009] or a pharmaceutically acceptable salt thereof wherein:

[0010] R¹ is hydrogen, methyl or ethyl;

[0011] R² is a hydrocarbon radical selected from straight and branchedchain alkyl of from 1-12 carbons or monocyclic aryl optionallycontaining 1 or more lower alkyl substituents of from 1-2 carbon atomsand/or 1 or more halogen (Cl, F or Br) substituents;

[0012] R′ is hydrogen or methyl;

[0013] R″ is hydrogen or β-methyl; and

[0014] R′″ is hydrogen, α-methyl or β-methyl.

[0015] In one class of this second embodiment, the 5α-reductase 2inhibitor compounds have the structural formula II

[0016] or a pharmaceutically acceptable salt thereof wherein

[0017] R¹ is hydrogen, or methyl; and

[0018] R³ is branched chain alkyl of from 4-8 carbons.

[0019] Representative compounds that may be employed in the presentinvention include the following:

[0020] 17β-(N-tert-butylcarbamoyl)-4-aza-5-α-androst- 1-en-3-one,

[0021] 17β-(N-isobutylcarbamoyl)-4-aza-5-α-androst-1-en-3-one,

[0022] 17β-(N-tert-octylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

[0023] 17β-(N-octylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

[0024] 17β-(N- 1,1-diethylbutylcarbamoyl)-4-aza-5-α-androst- 1-en-3-one,

[0025] 17β-(N-neopentylcarbamoyl)-4-aza-5α-androst-1-en-3-one,

[0026] 17β-(N-tert-amylcarbamoyl-4-aza-5α-androst-1-en-3-one, and

[0027] 17B-(N-tert-hexylcarbamoyl)-4-aza-5α-androst-1-en-3-one;

[0028] and the corresponding compounds wherein the 4-nitrogen issubstituted in each of the above named compounds by a methyl or an ethylradical.

[0029] Also included as representative compounds are any of the aboveindicated compounds having the N-branched chain alkyl substituentreplaced by a methyl, ethyl, propyl, i-propyl, butyl, phenyl; 2, 3 or 4tolyl, xylyl, 2-bromo or 2-chlorophenyl, 2-6-dichloro, or a2,6-dibromophenyl substituent.

[0030] The compounds of formula I and II described above can besynthesized according to procedures well known in the art, and which aredescribed, for example, in U.S. Pat. No. 4,760,071, EP 0 285,382 and EP0 285 383. The compound finasteride is currently available as aprescription pharmaceutical from Merck & Co. Inc. The synthesis offinasteride is described in U.S. Pat. No. 4,760,071. A further synthesisof finasteride is described in Synthetic Communications, 30 (17), p.2683-2690 (1990).

[0031] The present invention has the objective of providing methods oftreating the hyperandrogenic conditions of androgenic alopecia,including male pattern baldness and female pattern baldness, acnevulgaris, seborrhea, female hirsutism, and polycystic ovary syndrome bysystemic, oral, parenteral or topical administration of a 5α-reductase 2inhibitor in a dosage amount under 5 mg/day, and particularly, fromabout 0.01 mg/day to 3.0 mg/day, and more particularly 0.05 to 1 mg/day.The invention is further illustrated by dosages of about 0.05 to 0.2mg/day and specifically dosages of about 0.05, 0.1, 0.15 and 0.2 mg/day.Exemplifying the invention are dosages of 0.05 and 0.2 mg/day. The term“treating androgenic alopecia” is intended to include the arrestingand/or reversing of androgenic alopecia, and the promotion of hairgrowth. Also, a 5α-reductase 2 inhibitor, e.g. finasteride, at a dosageunder 5 mgs/day can be used in combination with a potassium channelopener, such as minoxidil or a pharmaceutically acceptable salt thereof,for the treatment of androgenic alopecia, including male patternbaldness. The 5α-reductase 2 inhibitor and the potassium channel openermay both be applied topically, or each agent can be given via differentadministration routes; for example, the 5α-reductase 2 inhibitor may beadministered orally while the potassium channel opener may beadministered topically.

[0032] The present invention also has the objective of providingsuitable systemic, oral, parenteral and topical pharmaceuticalformulations for use in the novel methods of treatment of the presentinvention. The compositions containing 5α-reductase 2 inhibitorcompounds as the active ingredient for use in the treatment of theabove-noted hyperandrogenic conditions can be administered in a widevariety of therapeutic dosage forms in conventional vehicles forsystemic administration. For example, the compounds can be administeredin such oral dosage forms as tablets, capsules (each including timedrelease and sustained release formulations), pills, powders, granules,elixirs, tinctures, solutions, suspensions, syrups and emulsions.Likewise, they may also be administered in intravenous (both bolus andinfusion), intraperitoneal, subcutaneous, topical with or withoutocclusion, or intramuscular form, all using forms well known to those ofordinary skill in the pharmaceutical arts. For oral administration, forexample, the compositions can be provided in the form of scored orunscored tablets containing 0.01, 0.05, 0.1, 0.2, 1.0, 2.0 and 3.0milligrams of the activtingredient for the symptomatic adjustment of thedosage to the patient to be treated.

[0033] For the treatment of androgenic alopecia including male patternbaldness, acne vulgaris, seborrhea, and female hirsutism, the5α-reductase 2 inhibitor compounds may be administered in apharmaceutical composition comprising the active compound in combinationwith a pharmaceutically acceptable carrier adapted for topicaladministration. Topical pharmaceutical compositions may be, e.g., in theform of a solution, cream, ointment, gel, lotion, shampoo or aerosolformulation adapted for application to the skin. Topical pharmaceuticalcompositions useful in the method of treatment of the present inventionmay include about 0.001% to 0.1% of the active compound in admixturewith a pharmaceutically acceptable carrier.

[0034] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily. Thecompounds for the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches well known tothose of ordinary skill in that art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

[0035] The dosage regimen utilizing the compounds of the presentinvention is selected in accordance with a variety of factors includingtype, species, age, weight, sex and medical condition of the patient;the severity of the condition to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound thereof employed. A physician or veterinarian ofordinary skill can readily determine and prescribe the effective amountof the drug required to prevent, counter, arrest or reverse the progressof the condition. Optimal precision in achieving concentration of drugwithin the range that yields efficacy without toxicity requires aregimen based on the kinetics of the drug's availability to targetsites. This involves a consideration of the distribution, equilibrium,and elimination of a drug.

[0036] In the methods of the present invention, the 5α-reductase 2inhibitor compounds herein described in detail can form the activeingredient, and are typically administered in admixture with suitablepharmaceutical diluents, excipients or carriers (collectively referredto herein as “carrier” materials) suitably selected with respect to theintended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

[0037] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Capsules containing the product of thisinvention can be prepared by mixing an active compound of the presentinvention with lactose and magnesium stearate, calcium stearate, starch,talc, or other carriers, and placing the mixture in gelatin capsule.Tablets may be prepared by mixing the active ingredient withconventional tableting ingredients such as calcium phosphate, lactose,corn starch or magnesium stearate. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like.

[0038] The liquid forms in suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methyl-cellulose and the like. Other dispersing agents which maybe employed include glycerin and the like. For parenteraladministration, sterile suspensions and solutions are desired. Isotonicpreparations which generally contain suitable preservatives are employedwhen intravenous administration is desired.

[0039] Topical preparations containing the active drug component can beadmixed with a variety of carrier materials well known in the art, suchas, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, propylene glycol, PPG2 myristyl propionate, and thelike, to form, e.g., alcoholic solutions, topical cleansers, cleansingcreams, skin gels, skin lotions, and shampoos in cream or gelformulations. See, e.g., EP 0 285 382.

[0040] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

[0041] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0042] The following example illustrates the present invention and assuch are not to be considered as limiting the invention set forth in theclaims appended hereto.

EXAMPLE 1

[0043] Finasteride is known to occur in two distinct polymorphic crystalforms, termed “form 1” and “form II”. Form I is the marketed form offinasteride as a 5 mg tablet (PROSCAR®).

[0044] Finasteride Form I can be prepared by dissolving finasteride inglacial acetic acid (ca. 100 mg/ml) and adding water with stirring untilthe weight % of water equals or exceeds 84%. The resulting solid phaseis collected by filtration and dried under vacuum and at about 50° C.The resulting Form I is characterized by a differential scanningcalorimetry (DSC) curve, at heating rate of 20° C./min and in a closedcup, exhibiting a minor endotherm with a peak temperature of about 232°C., an extrapolated onset temperature of about 223° C. with anassociated heat of about 11 joules/gm and by a major melting endothermwith a peak temperature of about of 261° C., an extrapolated onsettemperature of about 258° C. with an associated heat of about 89 J/gm.The x-ray powder diffraction pattern is characterized by d-spacings of6.44, 5.69, 5.36, 4.89, 4.55, 4.31, 3.85, 3.59 and 3.14 . The FT-IRspectrum shows bands at 3431, 3237, 1692, 1666, 1602 and 688 cm-1. Thesolubilities in water and cyclohexane at 25° C. are 0.05+0.02 and0.27+0.05 mg/gm respectively. In addition, Form I of finasteride can beprepared by recrystallization from dry (H₂O<1 mg/ml) ethyl acetate andisopropyl acetate. The isolated solids are dried under vacuum at about50° C. and have the same physical characterization data as given above.

EXAMPLE 2

[0045] Form II of fmasteride can be prepared by dissolving finasteridein glacial acetic acid (ca. 100 mg/ml) and adding water with stirringuntil the weight % of water equals about 75% but not in excess of 80%.The resulting solid phase is collected by filtration and dried undervacuum and at about 100° C. The resulting Form II is characterized by aDSC curve, at heating rate of 20° C./min and in a closed cup, exhibitinga single melting endotherm with a peak temperature of about of 261° C.,an extrapolated onset temperature of about 258° C. with an associatedheat of about 89 J/gm. The x- ray powder diffraction pattern ischaracterized by d-spacings of 14.09, 10.36, 7.92, 7.18, 6.40, 5.93,5.66, 5.31, 4.68, 3.90, 3.60 and 3.25. The FT-IR spectrum shows bands at3441, 3215, 1678, 1654, 1597, 1476 and 752 cm-1. The solubilities inwater and cyclohexane at 25° C. are 0.16+0.02 and 0.42+0.05 mg/gmrespectively. In addition, Form II of finasteride can be prepared byrecrystallization from ethyl acetate containing between 2 to 30 mg/ml ofwater and isopropyl acetate containing between 2 to 15 mg/ml of water.The isolated solids are dried under vacuum at about 80° C. and have thesame physical characterization data as given above. Form II can also beprepared by heating Form I up to about 150° C., holding for about onehour and cooling back to room temperature. The Form II prepared in thismanner has the same physical characterization data as given above.

EXAMPLE 3 Preparation of Human Prostatic 5α-reductase.

[0046] Samples of human tissue were pulverized using a freezer mill andhomogenized in 40 mM potassium phosphate, pH 6.5, 5 mM magnesiumsulfate, 25 mM potassium chloride, 1 mM phenylmethyl-sulfonyl fluoride,1 mM dithiothreitol (DTT) containing 0.25 M sucrose using aPotter-Elvehjem homogenizer. A crude nuclear pellet was prepared bycentrifugation of the homogenate at 1,500×g for 15 min. The crudenuclear pellet was washed two times and resuspended in two volumes ofbuffer. Glycerol was added to the resuspended pellet to a finalconcentration of 20%. The enzyme suspension was frozen in aliquots at−80° C. The prostatic reductases were stable for at least 4 months whenstored under these conditions.

50α-reductase Assay

[0047] The reaction mixture for the type 2 5α-reductase contained 40 mMsodium citrate, pH 5.5, 0.3 μM [7-³H]-testosterone, 1 mM dithiothreitoland 500 μM NADPH in a final volume of 100 μl. Typically, the assay wasinitiated by the addition of 50-100 μg prostatic homogenate andincubated at 37° C. After 10-50 min the reaction was quenched byextraction with 250 μl of a mixture of 70% cyclohexane: 30% ethylacetate containing 10 μg each DHT and T. The aqueous and organic layerswere separated by centrifugation at 14,000 rpm in an Eppendorfmicrofuge. The organic layer was subjected to normal phase HPLC (10 cmWhatman partisil 5 silica column equilibrated in 1 ml/min 70%cyclohexane: 30% ethyl acetate; retention times: DHT, 6.8-7.2 min;androstanediol, 7.6-8.0 min; T, 9.1-9.7 min). The HPLC system consistedof a Waters Model 680 Gradient System equipped with a Hitachi Model 655Aautosampler, Applied Biosystems Model 757 variable UV detector, and aRadiomatic Model A120 radioactivity analyzer. The conversion of T to DHTwas monitored using the radioactivity flow detector by mixing the HPLCeffluent with one volume of Flo Scint 1 (Radiomatic). Under theconditions described, the production of DHT was linear for at least 25min. The only steroids observed with the human prostate preparation wereT, DHT and androstanediol.

Inhibition Studies

[0048] Compounds were dissolved in 100% ethanol. IC₅₀ values representthe concentration of inhibitor required to decrease enzyme activity to50% of the control. IC₅₀ values were determined using a 6 pointtitration where the concentration of the inhibitor was varied from 0.1to 1000 nM.

EXAMPLE 4 MACROPHOTOGRAPHY AND GLOBAL PHOTOGRAPHY PROCEDURE FORDETECTION OF HAIR GROWTH

[0049] A. Macrophotographic Procedure

[0050] Location: ID card

[0051] Haircount target area

[0052] Equipment: Film: Kodak-T-max 24 exposure each of same emulsionlot number

[0053] Camera: Nikon N-6000

[0054] Lens: Nikkor 60 mm f2.8

[0055] Flashes: Nikon SB-21B Macroflash

[0056] Device: registration device

[0057] Photographic Procedure:

[0058] In these clinical photographs, the only variable allowed is thehaircount. Film emulsion, lighting, framing, exposure, and reproductionratios are held constant.

[0059] 1. The haircount area on the patient is prepared as follows:

[0060] A small (˜1mm) dot tattoo is placed at the beginning of the studyat the leading edge of the bald area directly anterior to the center ofthe vertex bald spot, using a commercial tattooing machine or manually(needle and ink). An area approximately one square inch in size,centered at the tattoo at the leading edge of the balding area, isclipped short (˜2mm). Cut hairs are removed from the area to bephotographed, using tape. Compressed air and/or ethanol wipes may alsobe used to facilitate removal of cut hairs.

[0061] 2. Magnification: Each lens supplied has a fixed reproductionratio of 1:1.2.

[0062] Aperture: Every photograph is taken at f/22.

[0063] Film: T-Max 100 (24 exposure) is used.

[0064] 3. Patient's haircount target area. Three exposures (−⅔, 0, and+⅔ f-stop).

[0065] A trained technician places a transparency over the photographicprint and, using a felt tip pen, places a black dot over each visiblehair. The dot map transparency is then counted using image analysis withcomputer assistance.

[0066] Photographs are coded with a random number corresponding to studysite, visit number and patient allocation number to insure blinding totime. At Month 6, baseline and Month 6 photographs are counted and dataanalyzed for interim analysis. At Month 12, baseline, Month 6 and Month12 photographs are counted and data analyzed for the primary endpoint.

[0067] Methodology for detection of hair growth is also described inOlsen, E.A. and DeLong, E., J. American Academy of Dermatology, 30 Vol.23, p. 470 (1990).

[0068] B. Global Photographic Procedure

[0069] Locations: Color card/patient Id

[0070] Global photograph

[0071] Equipment: Film: Kodachrome KR-64 24 exposure each of sameemulsion lot number

[0072] Camera: Nikon N-6000

[0073] Lens: Nikkor 60 mm f2.8

[0074] Flashes: Nikon SB-23

[0075] Photographic Procedure

[0076] In these clinical photographs, the only variable allowed is theglobal area's appearance. Anything extraneous to the area (clothing,furniture, walls, etc.) is eliminated from the fields to bephotographed.

[0077] 1. Patients will have global photographs taken prior to hairclipping with the head in a fixed position (determined by the suppliedstereotactic device). Hair on the patient's head is positionedconsistenty so as to not obscure the bald area.

[0078] 2. Magnification: Each lens supplied has a fixed reproductionratio of 1:6.

[0079] Aperture: Every photograph will be taken at f/11.

[0080] Film: Kodachrome (24 exposure) is used.

[0081] 3. Patient's global photographs. Three exposures at zerocompensation.

[0082] Using the above-described methodology, it can be shown thatadministration of 5α-reductase 2 inhibitors, including finasteride, indosages below 5 mg/day per patient, for example, 1 mg/day or 0.2 mg/day,are useful in the treatment of androgenic alopecia, and promote hairgrowth in patients with this condition.

EXAMPLE 5

[0083] In another test, finasteride was orally administered for 6 weeksto men with male pattern baldness at doses of 0.2 mg/day, 1.0 mg/day and5.0 mgs/day. The results of this test showed a significant reduction inDHT content in scalp tissue of the test participants.

What is claimed is:
 1. A method of treating androgenic alopeciacomprising administering to a person in need of such treatment a5α-reductase 2 inhibitor in a dosage amount under 5.0 mgs/day.
 2. Themethod of claim 1 wherein the dosage amount is from about 0.01 to 3.0mgs/day.
 3. The method of claim I wherein the dosage amount is fromabout 0.05 to 1.0 mg/day.
 4. The method of claim 1 wherein the dosageamount is about 0.05 mg/day.
 5. The method of claim 1 wherein the dosageamount is about 0.2 mgs/day.
 6. The method of claim 1 wherein theandrogenic alopecia is male pattern baldness.
 7. The method of claim 1wherein the 5α-reductase 2 inhibitor is administered orally.
 8. Themethod of claim 1 wherein the 5α-reductase 2 inhibitor is administeredtopically.
 9. The method of claim 1 wherein the 5α-reductase 2 inhibitorhas the structural formula I

or a pharmaceutically acceptable salt thereof wherein: R¹ is hydrogen,methyl or ethyl; R² is a hydrocarbon radical selected from straight andbranched chain alkyl of from 1-12 carbons or monocyclic aryl optionallycontaining 1 or more lower alkyl substituents of from 1-2 carbon atomsand/or 1 or more halogen (Cl, F or Br) substitints.; R′ is hydrogen ormethyl; R″ is hydrogen or β-methyl; and R′″ is hydrogen, α-methyl orβ-methyl.
 10. The method of claim 1 wherein the 5α-reductase 2 inhibitorhas the structural formula II

or a pharmaceutically acceptable salt thereof wherein R¹ is hydrogen, ormethyl; and R³ is branched chain alkyl of from 4-8 carbons.
 11. A methodof treating androgenic alopecia comprising administering to a person inneed of such treatment17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-ene-3-one in a dosageamount under 5.0 mgs/day.
 12. The method of claim 11 wherein theandrogenic alopecia is male pattern baldness.
 13. The method of claim 11wherein the dosage amount is from about 0.01 to 3.0 mgs/day.
 14. Themethod of claim 11 wherein the dosage amount is from about 0.05 to 1.0mg/day.
 15. The method of claim 11 wherein the dosage amount is about0.05 mg/day.
 16. The method of claim 11 wherein the dosage amount isabout 0.2 mg/day.
 17. The method of claim 11 wherein the17p-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-ene-3-one is administeredtopically.
 18. The method of claim 11 wherein the17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-ene-3-one is administeredorally.
 19. The method of claim 18 wherein the dosage amount is about0.2 mg/day.
 20. The method of claim 18 wherein the dosage amount itabout 0.05 mg/day.
 21. A method of arresting and reversing androgenicalopecia comprising administering to a person in need of such treatmenta 5α-reductase 2 inhibitor in a dosage amount under 5.0 mgs/day.
 22. Amethod of lowering the level of 5α-dihydrotestosterone in human scalpcomprising administering to a person in need of such treatment a5α-reductase 2 inhibitor in a dosage amount under 5.0 mgs/day.
 23. Themethod of claim 22 wherein the dosage amount is from about 0.01 to 3.0mgs/day.
 24. The method of claim 22 wherein the dosage amount is fromabout 0.05 to 1.0 mg/day.
 25. The method of claim 22 wherein the dosageamount is about 0.05 mg/day.
 26. The method of claim 22 wherein thedosage amount is about 0.2 mg/day.
 27. The method of claim 22 whereinthe dosage amount is about 1.0 mg/day.